ORMDL3基因多态性与哮喘相关性的研究进展

支气管哮喘是一种有明显家族聚集倾向的多基因遗传病，它的发生既受遗传因素又受环境因素的影响，至今约有100多个哮喘候选基因被发现，且多个已得到可靠的实验验证。Miram等。于2007年首次通过全基因组关联研究发现血清类黏蛋白1样蛋白3（ORMDL3）基因是同年研究中与哮喘相关度最高的易感基因，且该基因与哮喘的关联性已在多个种族中得到验证。了解ORMDL3与哮喘的相关性及其作用机制可能为哮喘的发生机制、早期诊断、治疗及一级预防提供新方向。现就该哮喘易感基因及其研究进展综述如下。     

一种新的哮喘易感性基因——哮喘易感性G蛋白耦联受体

哮喘是一种多基因遗传病,近来发现许多染色体区域的多种基因与哮喘相关。哮喘易感性G蛋白耦联受体（G protein-coupled receptor for asthma susceptibility,GPRA）是新近发现的一种与哮喘易感性相关的候选基因。研究发现该基因的多态性与哮喘、支气管高反应性和血清高IgE水平相关。GPRA基因编码的产物属于G蛋白耦联受体超家族（GPCR）,其可编码七种不同的蛋白亚型。     

支气管哮喘遗传学的最新研究进展

哮喘是一种多基因遗传学疾病,由许多易感基因和环境因素共同作用而发病。本文就哮喘易感基因及其确定方法的最新进展进行综述。①基因组扫描是从基因组扫描病例和家系入手,用分布在全部染色体上的数十乃至数百个分子标记对家系全体成员进行连锁分析、连锁不平衡分析和传递不平衡检验。该类研究发现了20个基因组区域都包含哮喘易感性基因,如:ETS-2、ETS-3、ADAM-33、PHF11、PCDH1等;②侯选基因法指对疾病病理发生的各个环节进行详细调查,确定最有可能与疾病表现相关的功能蛋白,先对其基因和邻近的遗传标记做相关分析,进而找出与发病一致的突变。如染色体5q31-33的细胞因子簇,6号染色体的HLA,染色体2q33的CTLA4等发现在哮喘发生中可能起着重要作用。     

哮喘与β_2肾上腺素受体基因多态性

哮喘发病受多个基因及环境因素的共同影响。位于染色体5q上的β_2肾上腺素受体基因虽然并非哮喘发病的决定因素,但研究证明其单核苷酸多态性与夜间哮喘、哮喘的严重程度及激素倚赖性哮喘等相关,还可影响受体对激动剂的亲和力及激动剂引起的受体作用的下调。     

基因芯片筛选7例患儿哮喘基因的研究

目的对7例支气管哮喘(简称哮喘)患儿的差异表达基因进行生物信息学分类。方法实验组7例,对照组8例,抽取外周血并分离出淋巴细胞RNA,进行cDNA合成、标记及杂交,通过聚类分析来揭示标本之间可辨识的基因表达谱,最后用GO分析和Pathway分析测定这些差异表达基因的作用。结果在29890个基因中,发现4725个基因存在差异表达,其中1660个表达上调,3065个表达下调。GO分析发现这些基因在生物学过程、细胞组分及分子功能中存在不同的调节。Pathway通路分析发现共有88条通路,其中基因表达上调通路有22条,下调有66条,进一步对这些通路的差异表达基因进行分析,发现有不少在3条以上的通路富集。结论实验组基因表达与对照组相比存在很大差异,这些差异基因涉及多种生物学过程,表明小儿哮喘的发病是一个复杂的病理生理过程。     

029 哮喘与β2肾上腺素受体基因多态性

哮喘发病受多个基因及环境因素的共同影响.位于染色体5cq上的β2肾上腺素受体基因虽然并非哮喘发病的决定因素,但研究证明其单核苷酸多态性与夜间哮喘、哮喘的严重程度及激素倚赖性哮喘等相关,还可影响受体对激动剂的亲和力及激动剂引起的受体作用的下调.     

支气管哮喘的遗传学研究进展

支气管哮喘(简称哮喘)是一种多基因遗传性疾病.候选基因和染色体定位是研究哮喘遗传学发病机制的两个主要环节.哮喘的候选基因分为免疫识别基因、转录因子基因、受体基因、细胞因子基因和调节物基因共五大类.人类有多条染色体上的基因与哮喘相关,主要定位在染色体5q,6p和11q等.     

支气管哮喘患者IgE高亲和力受体β链基因多态性与血清总IgE关系的研究

IgE高亲和力受体β链(FcεRIβ)基因定位于染色体11q13区,被认为是特应性和支气管哮喘(简称哮喘)易感性的主要候选基因之一[1]。FcεRIβ基因存在数个单一核苷酸变异的多态性位点[2],其中Ile/Leu181、Val/Leu183、Glu/Gly237的3个位点与哮喘相关研究国内已有报道,而启动子区-109C/T位点的研究报道较少,我们应用聚合酶链反应限制性片段长度多态性(PCRRFLP)方法对-109C/T位点进行分析,研究江西籍汉族人群中该位点与哮喘发病及其血清总IgE水平之间的关系。对象与方法　哮喘组45例,男21例,女24例,年龄6～65岁。为江西医学院第二附属…     

哮喘与β2肾上腺素受体基因多态性

哮喘发病受多个基因及环境因素的共同影响，位于染色体5q上的β2肾上腺素受体基因虽然并非哮喘发病的决定因素，但研究证明其单核苷酸多态性与液间哮喘，哮喘的严重速度及激素倚赖性哮喘等相关，还可影响受体对激动剂的新和力及激动剂引起的受体作用的下调。     

支气管哮喘的遗传学研究进展

支气管哮喘（简称哮喘）是一种多基因遗传性疾病.候选基因和染色体定位是研究哮喘遗传学发病机制的两个主要环节.哮喘的候选基因分为免疫识别基因、转录因子基因、受体基因、细胞因子基因和调节物基因共五大类.人类有多条染色体上的基因与哮喘相关,主要定位在染色体5q,6p和11q等.     

Genome-wide association studies for discovery of genes involved in asthma

Asthma is the result of a complex interaction between environmental factors and genetic variants that confer susceptibility. Studies of the genetics of asthma have previously been conducted using linkage designs and candidate gene association studies. Recently, the association study design has been extended from specific candidate genes to an unbiased genome-wide approach: the genome-wide association study (GWAS). To date, there have been 12 GWAS to look for susceptibility loci for asthma and related traits. The first GWAS for asthma discovered a novel associated locus on chromosome 17q21 encompassing the genes ORMDL3, GSDMB and ZPBP2. None of these genes would have been selected in a candidate association study based on current knowledge of the functions of these genes. Nevertheless, this finding has been consistently replicated in independent populations of European ancestry and also in other ethnic groups. Thus, chromosome 17q21 seems to be a true asthma susceptibility locus. Other genes that were identified in more than one GWAS are IL33, RAD50, IL1RL1 and HLA-DQB1. Additional novel susceptibility genes identified in a single study include DENND1BI and IL2RB. Discovering the causal mechanism behind these associations is likely to yield great insights into the development of asthma. It is likely that further meta-analyses of asthma GWAS data from existing international consortia will uncover more novel susceptibility genes and further increase our understanding of this disease.     

Genome-Wide Association Studies of Asthma

Bronchial asthma is a common inflammatory disease caused by a combination of genetic and environmental factors. To discover the genes and cellular pathways underlying asthma, a large number of genetic studies have been conducted. Genome-wide association studies (GWAS), which comprehensively assess genes related to multifactorial diseases and drug reactivity, have enhanced understanding of human diseases. From 2007, GWAS of susceptibility to asthma in Caucasian, Mexican, and African-ancestry populations have been conducted and several susceptible loci were identified. Recently, much larger consortium-based GWAS analyses of collaborative samples with adequate statistical power were performed, and the implicated genes suggested a role for communication of epithelial damage to the adaptive immune system and activation of airway inflammation. Furthermore, GWAS identified candidate loci associated with natural variations in lung function, blood eosinophilia and eosinophilic esophagitis, which is inflammation of the esophagus with abnormal infiltration of eosinophils in an allergic reaction. Comparing GWAS in asthma and these clinical phenotypes might help to clarify the mechanisms underlying asthma. Pharmacogenomics analyses using GWAS regarding genetic factors related to the effectiveness of inhaled corticosteroid (ICS) therapy and inhaled beta₂-adrenergic agonists are ongoing now. Although a more complete collection of associated genes and pathways is needed, biologic insights revealed by GWAS provide valuable insights into the pathophysiology of asthma and contribute to the development of better treatment and preventive strategies.     

Advances in the genetics of sarcoidosis

Familial aggregation and racial differences in incidence support the notion that sarcoidosis occurs in genetically susceptible hosts. Siblings of those affected with sarcoidosis have a modestly increased disease risk, with an odds ratio of about 5. HLA genes have been the most extensively studied susceptibility genes in sarcoidosis. Many other attractive candidate genes have been evaluated using the case-control study design, but few have been confirmed. Confounding by population stratification likely explains much of the failure to replicate initial findings. A genomewide scan performed in German families with follow-up fine mapping studies has yielded a highly attractive candidate gene, BTNL2 in the MHC II region on chromosome 6. BTNL2, a member of the B7 family of costimulatory molecules, likely functions to down-regulate T-cell activation. A BTNL2 single-nucleotide polymorphism associated with sarcoidosis is predicted to result in a truncated nonfunctioning protein. Association of BTNL2 with sarcoidosis has been confirmed in both white and African Americans. A genomewide scan with follow-up fine mapping studies in African American families has identified chromosome 5 as potentially harboring candidate genes. Additional linkage analysis in the African American families stratified according to genetic ancestry demonstrated that linkage signals varied according to degree of admixture. Certain chromosomal regions were also found linked to specific phenotypes. Follow-up fine mapping studies of the linked regions are underway.     

Genotype predictors of response to asthma medications.

The search for the genetic basis of asthma and other allergic diseases has identified many candidate genes. Some of these genes have been investigated to determine whether they influence a person's response to asthma medication. Several studies have shown that polymorphisms in the beta 2 -adrenergic receptor gene influence responsiveness to beta-agonists. Polymorphisms in the 5-lipoxygenase gene and the leukotriene C 4 synthase gene have been associated with response to medications that target leukotriene metabolism. Results such as these suggest the potential for pharmacogenetic tailoring of therapy for individual asthmatic patients. To date, no polymorphisms have been identified that influence response to anticholinergics or are involved in steroid resistance.     

Update on the genetics of spondyloarthritis--ankylosing spondylitis and psoriatic arthritis

Spondyloarthritis refers to a group of inflammatory rheumatic diseases that share common clinical and genetic characteristics. Due to the rapid advances in technology and computational genetics, there is now an increasing list of well-validated genes in spondyloarthritis. The newest genetic associations are of modest magnitude and have been identified as a result of analysing thousands of samples, using genome-wide association scans or targeted candidate-gene association studies. In this article, we will highlight the genes associated with spondyloarthritis, with an emphasis on the recent candidate genes that have been identified in ankylosing spondylitis and psoriatic arthritis. If applicable, we will also discuss their potential relevance to the clinical rheumatologist.     

Recent advances in the study of genes involved in non-syndromic premature ovarian failure

Premature ovarian failure (POF) is a common pathology leading to infertility affecting about 1% of women under 40 years old. In POF patients, the ovarian dysfunction is characterized by the lack of the ovarian response to close a negative feedback loop on the synthesis of pituitary gonadotropins. Although the majority of cases are considered as idiopathic, diverse aetiologies have been associated, including genetic factors. Up to now, the potential genetic causes of non-syndromic POF have been established mainly by genetic linkage analysis of familial cases or by the screening of mutations in candidate genes based on animal models. Here, we review recent advances in the study of candidate genes.     

Genetic factors in psoriatic arthritis

The genetic factors that are associated with psoriatic arthritis (PsA) are intricately linked with those that predispose to psoriasis itself. The strongest association is with human leukocyte antigen-Cw*0602, although true susceptibility may lie with one of the neighboring genes along a disease-associated haplotype. There are a number of interesting candidate genes within the major histocompatibility complex (MHC) region with strong functional relevance that have been investigated in PsA. In addition, several areas outside the MHC complex have been highlighted as a result of genetic linkage studies in psoriasis. PsA is a complex, multifactorial disease where multiple genes are likely to influence disease susceptibility, severity, and clinical phenotype. The current evidence for genetic factors in psoriasis and PsA will be reviewed.     

基于网络的哮喘易感基因研究新策略

哮喘易感基因的研究正在世界各地许多实验室蓬勃开展,由于此种疾病的复杂性和异质性等原因,哮喘易感基因的鉴定依然任重而道远。目前的研究表明,哮喘所涉及的染色体达10多条,与其关联或连锁的候选易感基因多达170多个,但多数研究结果的一致性和重复性较差。分析其中的原因,除了哮喘的复杂性、种族的差异、病例的选择与分层的不同外,研究策略、技术路线和方法应该是导致结果不一致的主要原因之一。本文基于系统生物学理论与候选基因的方法,系统阐述一种哮喘易感基因研究的新策略。